Variant NM_012203.2:c.404+3_404+6delAAGT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_012203.2(GRHPR):c.404+3_404+6delAAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,582,228 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GRHPR
NM_012203.2 splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 9.26

Variant links:

Genes affected

GRHPR (HGNC:4570): (glyoxylate and hydroxypyruvate reductase) This gene encodes an enzyme with hydroxypyruvate reductase, glyoxylate reductase, and D-glycerate dehydrogenase enzymatic activities. The enzyme has widespread tissue expression and has a role in metabolism. Type II hyperoxaluria is caused by mutations in this gene. [provided by RefSeq, Jul 2008]

GRHPR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]

PP5

Variant 9-37426652-GAAGT-G is Pathogenic according to our data. Variant chr9-37426652-GAAGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37426652-GAAGT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHPR	NM_012203.2 link	c.404+3_404+6delAAGT		splice_region_variant, intron_variant	Intron 4 of 8	ENST00000318158.11	NP_036335.1	Q9UBQ7-1A0A384N605

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHPR	ENST00000318158.11 link	c.403_404+2delAAGT	p.Asn135ValfsTer29	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 4 of 9	1	NM_012203.2	ENSP00000313432.6		Q9UBQ7-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251320

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1430038

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

713524

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000934

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000739

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type II

Pathogenic:7Other:1

Jul 02, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 19, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_012203.1(GRHPR):c.404+3_404+6delAAGT is classified as likely pathogenic in the context of primary hyperoxaluria type 2. Sources cited for classification include the following: PMID 24116921 and 14635115. Classification of NM_012203.1(GRHPR):c.404+3_404+6delAAGT is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and the incidence of disease is extremely low. Please note: this variant was assessed in the context of healthy population screening. -

Aug 03, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GRHPR c.404+3_404+6delAAGT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. These predictions have been confirmed by experimental evidence that this variant affects mRNA splicing (Cregeen_2003). The variant allele was found at a frequency of 2.8e-05 in 246140 control chromosomes. c.404+3_404+6delAAGT has been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 2, and has been reported as a common pathogenic variants in individuals of Asian ancestry (Cregeen_2003, Webster_2000, Williams_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 26, 2024

Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant_type:truncating/MutationTaster:NONE/CADD:NONE/phyloP:NONE/phastCons:NONE/gnomAD_exome_EastAsian:NONE/ExAC_EastAsian:NONE/dbSNP:NONE -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

May 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 of the GRHPR gene. It does not directly change the encoded amino acid sequence of the GRHPR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs180177309, gnomAD 0.01%). This variant has been observed in individuals with primary hyperoxaluria type 2 (PMID: 11030416, 14635115). This variant is also known as c.403_405+2delAAGT. ClinVar contains an entry for this variant (Variation ID: 204250). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 14635115). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.54

Position offset: 21

DS_DL_spliceai

0.94

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over